The long term goal of this project is to establish the normal physiologic role of the cyclic secretory pattern by the islets of Langerhans. These studies will provide the foundation for assessment of its potentail pathophysiologic significance in Diabetes Mellitus, obesity, and other disorders of metabolic regulation. The impact of oscillating hormonal signals upon target tissues will be compared to provision of the same signals in a constant mode. Using conscious non-human primates, in vivo studies will test the effect of cyclic insulin and glucagon on hepatic metabolism, with respect to identification of pathways entrained, overall dose response characteristics and ability to respond rapidly and maximally to acute stimuli. The effect of cyclic insulin upon total body insulin responses will be studied in normal and insulin deficient, streptozotocin treated animals. Parallel studies of the cyclic delivery of hormones will be done in vitro using perifused target tissues; isolated rat hepatocytes, adipocytes and intact EDL or Soleus muscles. The in vitro models will be used for study of the time constants for entrainment of specific hormone sensitive pathways, the effects of altered phase or frequency of signals, effects of conditioning to cyclic delivery of hormone upon hormone sensitivity, upon the efficiency of metabolic conversion per unit oxygen consumed and upon receptor numerical regulation and intracellular processing.